CN101143855A - 合成n-[(s)-1-羧基丁基]-(s)-丙氨酸酯的新方法及该化合物在合成培哚普利中的用途 - Google Patents
合成n-[(s)-1-羧基丁基]-(s)-丙氨酸酯的新方法及该化合物在合成培哚普利中的用途 Download PDFInfo
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- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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Abstract
本发明公开合成式(I)衍生物的方法，在式(I)中，R代表直链或支链(C1－C6)烷基基团。本发明的方法可用于合成培哚普利及其药学可接受盐。
Description
本申请为2004年8月31日提交的、发明名称为“合成N-[(S)-1-羧基丁基]-(S)-丙氨酸酯的新方法及该化合物在合成培哚普利中的用途”的PCT申请PCT/FR2004/002213的分案申请，所述PCT申请进入中国国家阶段的日期为2006年2月16日，申请号为200480023534.0。
技术领域
本发明涉及合成N-[(S)-1-羧基丁基]-(S)-丙氨酸酯的方法，以及它们在合成培哚普利及其药学可接受盐中的用途。
更具体地讲，本发明涉及合成下式(I)衍生物以及它们与一种或多种无机或有机酸或碱的加成盐的新方法：
式中R代表直链或支链(C1-C6)烷基基团。
根据本发明方法得到的式(I)化合物可用于合成下式(II)培哚普利及其药学可接受盐：
培哚普利及其盐具有重要的药理学性质。
背景技术
它们的主要性质是抑制血管紧张素I转化酶(或激肽酶II)，因此，一方面它们能够阻止十肽血管紧张素I转化成八肽血管紧张素II(血管收缩剂)，另一方面它们能够防止缓激肽(血管舒张药)降解成失活肽。
这两种作用有助于培哚普利在心血管疾病、特别是动脉高血压和心脏供血不足中发挥有益的作用。
欧洲专利EP 0 049 658中描述了培哚普利、其制备方法及其在治疗中的用途。
鉴于这种化合物的药学价值，重要的是能够采用竞争力强的合成方法获得式(I)中间体，特别是能够选择性地获得非对映异构体(S，S)，其产率高，纯度极佳，而且还易转换成工业规模。
人们已经知道了一些制备式(I)化合物的方法。
-杂志《Tet.Lett.》，1982，23(16)，1677-80描述了在氰基硼氢化钠存在下，在乙醇中，使2-氧代戊酸乙酯与丙氨酸叔-丁酯反应获得式(I)化合物(R＝乙基)。
-专利EP 0 309 324描述了在二甲基甲酰胺中，在三乙胺存在下，使丙氨酸苄酯与α-溴代戊酸乙酯反应得到式(I)化合物(R＝乙基)。
-专利EP 0 308 340和EP 0 308 341描述了在水中，在氢、披钯炭和氢氧化钠存在下，使戊氨酸乙酯盐酸盐与丙酮酸反应得到式(I)化合物(R＝乙基)。
发明内容
本申请人现在已研制一种式(I)衍生物的新工业合成方法。
更具体地讲，本发明涉及合成式(I)化合物的方法，其特征在于使下式(III)吗啉酮：
式中P代表氨基官能团保护基团，
＊或者在碱存在下与溴化物或三氟甲磺酸烯丙酯反应得到具有(3S，5S)构型的下式(IV)化合物：
式中P如前面所定义，
该化合物在披钯炭的存在下进行氢化，
*或者与碘代丙烷反应得到具有(3S，5S)构型的下式(V)化合物：
式中P如前面所定义，
该化合物经LiOH作用，然后经酯化试剂作用，得到下式(VI)化合物：
式中R和P如前面所定义，
该化合物与氧化剂进行反应，在氨基官能团去保护后得到式(I)化合物。
在本发明可使用的氨基官能团保护基团中，作为非限制性实例可以列举叔-丁氧基羰基和苄氧基羰基基团。优选的P基团是叔-丁氧基羰基。
在式(III)化合物与溴化物或三氟甲磺酸烯丙酯的反应可使用的碱中，作为非限制性实例可以列举二异丙基氨化锂(LDA)、双(三甲基甲硅烷基)氨化钠(NaHMDS)和叔丁醇钾。
在制备式(VI)化合物可使用的酯化试剂中，作为优选可以列举下式(VII)化合物：
R-X (VII)
式中R如式(I)中所定义，X代表三氟甲磺酸酯、对甲苯磺酸酯或甲磺酸酯基团或卤素原子，优选碘原子。
希望得到其中R代表甲基的式(I)化合物时，酯化试剂也可以是重氮甲烷。
在式(VI)化合物的氧化反应可使用的氧化剂中，作为非限制性实例可以列举在RuCl3存在下的NaIO4。
这种氧化反应也可以分两步进行，第一步，例如在Swern条件下，将式(VI)化合物转化成相应的醛，第二步，例如用KMnO4将这种醛氧化成相应的羧酸。
在化学或药品工业中，特别是在培哚普利合成中，式(V)和(VI)化合物是用作合成中间体的新产品，因此是本发明的组成部分。
优选的R基团是乙基。
使用(S)-N-苄基丙氨醇可以得到式(III)化合物，在三乙胺存在下，使(S)-N-苄基丙氨醇与溴代乙酸乙酯进行反应，在苄基基团裂解后得到(S)-N-(乙氧基羰基甲基)丙氨醇，它再用如前面定义的P基团进行保护，然后通过与对-甲苯磺酸的反应进行环化。
具体实施方式
实施例：N-[(S)-乙氧羰基-1-丁基]-(S)-丙氨酸，盐酸盐
步骤A：(3S，5S)-3-烯丙基-5-甲基-2-氧代-4-吗啉羧酸叔丁酯：
向反应器中装入200g(5S)-5-甲基-2-氧代-4-吗啉甲酸叔丁酯和700ml四氢呋喃，然后将这种溶液冷却到-60℃，再添加700ml 2M二异丙基氨化锂在四氢呋喃和庚烷中的溶液，同时将该反应介质的温度保持低于-40℃。在反应1小时后，添加225g烯丙基溴，同时将反应介质的温度保持低于-30℃，搅拌3h。
然后使反应化合物升到室温，用氯化铵水溶液进行水解，用乙醚提取，其醚相用水洗涤。
该醚相经干燥分离得到的(3S，5S)-3-烯丙基-5-甲基-2-氧代-4-吗啉甲酸叔丁酯可原样用于后续步骤。
步骤B：(3S，5S)-5-甲基-3-丙基-2-氧代-4-吗啉甲酸叔丁酯：
向氢化器中装入200g在前面步骤得到的化合物在乙醇中的溶液，然后装入5g10％Pd/C。在大气压与室温下进行氢化直到吸收理论量的氢。
过滤除去催化剂，然后干燥分离(3S，5S)-5-甲基-3-丙基-2-氧代-4-吗啉甲酸叔丁酯。
步骤C：(2S)-2-{(叔-丁氧基羰基)[(1S)-2-羟基-1-甲基乙基]-氨基}-戊酸乙酯
向反应器中装入200g在前面步骤得到的化合物、500ml乙腈、500ml水和500ml己烷，然后添加33g氢氧化锂水合物，在0℃搅拌3h。
干燥所述反应混合物，得到的锂盐溶解在1.5升二甲基甲酰胺中，然后在室温下用122g碘乙烷进行处理。
在蒸去二甲基甲酰胺后，已干燥的残留物用乙醇处理，用二氧化硅过滤，得到(2S)-2-{(叔-丁氧基羰基)[(1S)-2-羟基-1-甲基乙基]-氨基}-戊酸乙酯，其产率60％。
步骤D：N-[(S)-乙氧基羰基-1-丁基]-N-(叔-丁氧基羰基)-(S)-丙氨酸
向反应器中装入500ml二氯甲烷、500ml水和500ml乙腈，然后添加141g高碘酸钠和1.35g三氯化钌水合物。搅拌1h，再快速添加200g在前面步骤得到的化合物。反应结束后，用硅藻土过滤，洗涤有机相，并将其蒸发至干，得到N-[(S)-乙氧基羰基-1-丁基]-N-(叔-丁氧基羰基)-(S)-丙氨酸。
步骤E：N-[(S)-乙氧基羰基-1-丁基]-(S)-丙氨酸，盐酸盐：
向反应器中装入200g在前面步骤得到的化合物和1.5升乙酸乙酯，然后将反应介质的温度调到0℃，通入盐酸气流30分钟。在室温下搅拌一夜后，生成的沉淀经过滤、漂洗和干燥得到N-[(S)-乙氧基羰基-1-丁基]-(S)-丙氨酸盐酸盐，为定量产率。
Claims (2)
1.式(V)化合物：
式中P代表叔-丁氧基羰基。
2.式(VI)化合物：
式中P代表叔-丁氧基羰基，且R代表乙基。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03292145A EP1362845B1 (fr) | 2003-09-01 | 2003-09-01 | Nouveau procédé de synthèse des esters de la N-((S)-1-carboxybutyl)-(S)-alanine et application à la synthèse du perindopril |
| EP03292145.4 | 2003-09-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2004800235340A Division CN100460382C (zh) | 2003-09-01 | 2004-08-31 | 合成n-[(s)-1-羧基丁基]-(s)-丙氨酸酯的新方法及该化合物在合成培哚普利中的用途 |
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| Publication Number | Publication Date |
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| CN101143855A true CN101143855A (zh) | 2008-03-19 |
| CN100577652C CN100577652C (zh) | 2010-01-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200710167579A Expired - Fee Related CN100577652C (zh) | 2003-09-01 | 2004-08-31 | 合成n-[(s)-1-羧基丁基]-(s)-丙氨酸酯的中间体及该化合物在合成培哚普利中的用途 |
| CNB2004800235340A Expired - Fee Related CN100460382C (zh) | 2003-09-01 | 2004-08-31 | 合成n-[(s)-1-羧基丁基]-(s)-丙氨酸酯的新方法及该化合物在合成培哚普利中的用途 |
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| CNB2004800235340A Expired - Fee Related CN100460382C (zh) | 2003-09-01 | 2004-08-31 | 合成n-[(s)-1-羧基丁基]-(s)-丙氨酸酯的新方法及该化合物在合成培哚普利中的用途 |
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| Country | Link |
|---|---|
| US (1) | US7361757B2 (zh) |
| EP (1) | EP1362845B1 (zh) |
| JP (1) | JP4616833B2 (zh) |
| KR (1) | KR100735198B1 (zh) |
| CN (2) | CN100577652C (zh) |
| AR (1) | AR045545A1 (zh) |
| AT (1) | ATE445588T1 (zh) |
| AU (1) | AU2004270432B8 (zh) |
| BR (1) | BRPI0413901B1 (zh) |
| CA (1) | CA2536926C (zh) |
| CY (1) | CY1109822T1 (zh) |
| DE (1) | DE60329648D1 (zh) |
| DK (1) | DK1362845T3 (zh) |
| EA (1) | EA009980B1 (zh) |
| EG (1) | EG25738A (zh) |
| ES (1) | ES2334900T3 (zh) |
| GE (1) | GEP20094650B (zh) |
| HK (2) | HK1096378A1 (zh) |
| MA (1) | MA28018A1 (zh) |
| MX (1) | MXPA06002229A (zh) |
| MY (1) | MY139073A (zh) |
| NO (1) | NO20061152L (zh) |
| NZ (1) | NZ545337A (zh) |
| PL (1) | PL211801B1 (zh) |
| PT (1) | PT1362845E (zh) |
| SI (1) | SI1362845T1 (zh) |
| UA (1) | UA81179C2 (zh) |
| WO (1) | WO2005023755A1 (zh) |
| ZA (1) | ZA200601427B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2603856T3 (es) * | 2004-03-29 | 2017-03-01 | Les Laboratoires Servier | Procedimiento para preparar una composición farmacéutica sólida |
| SI21800A (sl) | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nov postopek sinteze perindoprila |
| EP1792896A1 (en) | 2005-12-01 | 2007-06-06 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of perindopril and salts thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2503155A2 (fr) * | 1980-10-02 | 1982-10-08 | Science Union & Cie | Nouveaux imino diacides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme |
| FR2620699B1 (fr) * | 1987-09-17 | 1990-06-01 | Adir | Procede de synthese d'alpha amino acides n alkyles et de leurs esters. application a la synthese de carboxyalkyl dipeptides |
| FR2807037B1 (fr) * | 2000-03-31 | 2002-05-10 | Adir | NOUVEAU PROCEDE DE SYNTHESE DES ESTERS DE LA N-[(s)-1- CARBOXYBUTYL]-(S)-ALANINE ET APPLICATION A LA SYNTHESE DU PERINDOPRIL |
| FR2807430B1 (fr) * | 2000-04-11 | 2002-05-17 | Adir | Nouveau procede de synthese des esters de la n-[(s)-1- carboxybutyl]-(s)-alanine et application a la synthese du perindopril |
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- 2003-09-01 DK DK03292145.4T patent/DK1362845T3/da active
- 2003-09-01 SI SI200331694T patent/SI1362845T1/sl unknown
- 2003-09-01 AT AT03292145T patent/ATE445588T1/de active
- 2003-09-01 EP EP03292145A patent/EP1362845B1/fr not_active Expired - Lifetime
- 2003-09-01 DE DE60329648T patent/DE60329648D1/de not_active Expired - Lifetime
- 2003-09-01 ES ES03292145T patent/ES2334900T3/es not_active Expired - Lifetime
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- 2004-08-31 EA EA200600501A patent/EA009980B1/ru not_active IP Right Cessation
- 2004-08-31 US US10/569,472 patent/US7361757B2/en not_active Expired - Fee Related
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- 2004-08-31 WO PCT/FR2004/002213 patent/WO2005023755A1/fr active Application Filing
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